Opioid antagonists such as naloxone can precipitate withdrawal signs and symptoms when administered several hours after acute exposure to a short-acting opioid agonist drug. This observation is rather remarkable since withdrawal signs are generally associated with chronic exposure to opioid drugs, where they denote the presence of physical dependence. The antagonist precipitated withdrawal signs seen after brief exposure to agonist drug (antagonist sensitivity) may represent the incipient stages of opioid physical dependence. The human pharmacology of opioid antagonist sensitivity is the focus of the present grant project. Because this phenomenon has virtually unexplored in humans, the series of studies proposed will provide basic parametric information about the characteristics of antagonist effects after brief opioid agonist exposure and the relationship of these effects to opioid physical dependence. Nine studies are proposed during a four-year grant period. These studies will examine effects of repeated versus single antagonist administrations (Exp. 1), determine the time course of precipitated withdrawal effects after brief opioid exposure (Exp. 2-4), characterize dose-effect relationships for an agonist (Exp. 5) and antagonist (Exp. 6) drug, examine the influence of opioid addiction history (Exp. 5), evaluate effects of brief versus more prolonged agonist exposures (Exp. 7), and examine the pharmacologic specificity of antagonist effects after brief exposure to opioid and non-opioid drugs (Exp. 8, 9). Studies of antagonist sensitivity should provide new insights into the development of opioid physical dependence. It is surprising that systematic studies of this very interesting phenomenon have not been conducted in humans to date. The present project will fill this gap in our knowledge.